P726: MYELOID-DERIVED SUPPRESSOR CELLS AS POTENTIAL TARGETS FOR IMMUNE THERAPY IN CCUS AND LOW RISK MDS
Authors: S. Bentivegna, M. O. Holmström, M. H. Andersen, K. Grønbæk
Journal: HemaSphere (2022)

Background: Myeloid-derived suppressor cells (MDSC) are powerful immune suppressing cells that infiltrate the bone marrow (BM) microenvironment in myelodysplastic syndrome (MDS) and suppress both a potential immune response against the malignant HSPC and the normal hematopoiesis (Chen et al., 2013). Different groups reported an expansion of MDSC in MDS, and an increased number of MDSC is associated with disease progression (Chen et al., 2013; Kittang et al., 2016). MDSC mediate their immunoregulatory effects releasing immunosuppressive cytokines, such as TGFβ, and enzymes such as indoleamine 2,3-dioxygenase (IDO) and arginase (ARG) (Mondanelli et al., 2017). The presence of self-reactive T cells that specifically target immunosuppressive cells in both healthy donors and cancer patients has previously been described (Andersen, 2017). These cells, termed anti-regulatory T cells (anti-Tregs), recognize epitopes derived from immunosuppressive proteins such as IDO, ARG, which are expressed by MDSC (Andersen, 2018). We speculate that the stimulation of anti-Tregs cells using peptide-based vaccines can lead to the depletion of the immunosuppressive cells in the BM, and it will help to prevent disease progression in patients with clonal cytopenia of undetermined significance (CCUS) or MDS. Aims: The aim of this work was to characterize the immune cell composition of blood and BM samples from CCUS/MDS patients and investigate the presence of circulating anti-Treg cells in blood samples and their reactivity towards immunogenic peptides. Methods: Using flow cytometry we analyzed blood and BM samples from 20 patients (pts) with CCUS/MDS (10 CCUS and 10 low risk-MDS) and 6 elderly healthy controls (EHC). The presence of anti-Tregs was investigated in 7 pts, by ELISPOT assay on patient T cells that had been stimulated with epitopes derived from the immunosuppressive proteins ARG, IDO or TGFβ. Results: Although there were no significant differences in the percentage of MDSC in BM samples between controls and pts, the proportion of IDO+ and ARG+ MDSC in pts was significantly higher compared to EHC. In addition, there was a significantly higher percentage of CTLA-4+ and PD-1+ T cells present in the BM samples from pts compared to EHC. Interestingly, in the ELISPOT assay, 4 out the 7 pts showed a significant response towards the ARG peptide, 2 showed a response towards IDO peptide and in 4 of the patients there was a significant response towards the TGFβ peptide. Overall, of the 7 pts analyzed, 6 harbored T cells specific to one or more of the immunosuppressive proteins ARG, IDO and TGFβ (figure 1). Image:Summary/Conclusion: There is an increased proportion of activated MDSC in BM in pts with CCUS/MDS compared to EHC. As the immune checkpoint molecules are expressed after T cell activation, the increased percentage of CTLA-4+ and PD-1+ cells in pts BM suggests that there is a T cell immune response in the BM of pts with CCUS/MDS. The ELISPOTs showed that circulating anti-Tregs are present in CCUS/MDS patients. These results suggest, that the tumor specific immune response in patients with CCUS/MDS is present, albeit suppressed by (amongst others) MDSC. We speculate that therapeutic cancer vaccination targeting immunosuppressive cells such as MDSC by vaccination using e.g. IDO, ARG or TGFβ derived epitopes will incite an anti-regulatory immune response, which may break the local immune suppression in the BM and allow effector immune cells to exert killing of transformed cells.